WO2020151686A1 - Dérivé de n-hétéroaryl sulfonamide, préparation et utilisation associées dans le traitement de maladies auto-immunes - Google Patents

Dérivé de n-hétéroaryl sulfonamide, préparation et utilisation associées dans le traitement de maladies auto-immunes Download PDF

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WO2020151686A1
WO2020151686A1 PCT/CN2020/073362 CN2020073362W WO2020151686A1 WO 2020151686 A1 WO2020151686 A1 WO 2020151686A1 CN 2020073362 W CN2020073362 W CN 2020073362W WO 2020151686 A1 WO2020151686 A1 WO 2020151686A1
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fluorobenzyl
pyridin
propanesulfonamide
acid
piperidin
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PCT/CN2020/073362
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Chinese (zh)
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王晓路
胡永洲
叶青
胡秀爱
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杭州壹瑞医药科技有限公司
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Definitions

  • the invention belongs to the field of medicine, and relates to an N-heteroarylsulfonamide derivative as a Kv1.3 potassium channel inhibitor, a preparation method thereof, and a medicine for the treatment of autoimmune diseases mediated by Kv1.3 In the application.
  • Kv1.3 is an important subtype of the voltage-gated potassium channel Kv1 family, which is widely distributed in body tissues, including human T lymphocytes. Participate in a variety of physiological and pathological processes such as cell proliferation, migration, and apoptosis by regulating the potassium ion concentration [Toldi G.et al.Immunol Res.,2016,64(2):627-631].
  • the voltage-gated channel Kv1.3 is a 4-mer composed of 4 ⁇ subunits, that is, these subunits are assembled into a functional channel, in which the potassium ion-conducting hole is located in the center of the 4-mer.
  • Each subunit contains 6 transmembrane segments (S1-S6), a P loop and the N- and C-termini in the membrane.
  • S1-S6 transmembrane segments
  • P loop the N- and C-termini in the membrane.
  • the depolarization of the cell membrane is induced by the 4 arginines located in the S4 fragment, which then causes the channel to be opened and causes a conformational change.
  • Kv1.3 peptide blockers all act on the conduction holes at the outer end of the membrane, thereby inhibiting the conduction function of potassium ions [Chandy and Norton, Curr Opin Chen Biol, 2017, 38: 97-107] [Zhao et .al.Toxins(Basel),2015,7:1749-1764].
  • Kv1.3 is mainly expressed in T lymphocytes, and together with calcium-activated Kca3.1 potassium channels, it prevents depolarization of cell membranes.
  • T cells When T cells are activated, these channels produce potassium ions outflow, and through CRAC (Orai/Stim) channels, promote the inflow of calcium ions into the cytoplasm to counteract the outflow of cations.
  • CRAC Orai/Stim
  • NFAT transcription factor
  • the Kv1.3 and Kca3.1 channels in T cells are part of the cell membrane signal complex, that is, the extra-membrane stimulus signal is coupled to the signal cascade transmission within the T cell [Chandy and Norton, Curr Opin Chem Biol, 2017, 38:97-107].
  • naive T cells and central memory T cells up-regulate the expression level of Kca3.1 while the number of Kv1.3 has no significant change.
  • terminally differentiated effector memory T cells T EM
  • CD-45RA-expressing effector memory T cells T EMRA
  • selectively blocking Kca3.1 can inhibit the proliferation of naive T cells and central memory T cells (T CM ), thereby inhibiting the production of corresponding cytokines.
  • Kv1.3 can inhibit the proliferation of effector memory T cells (T EM and T EMRA ) and the production of corresponding cytokines, and also inhibit the migration of T cells in vivo, but does not affect the Kca3 .1
  • T EM and T EMRA effector memory T cells
  • T CM central memory T cells
  • autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type I diabetes and psoriasis
  • the naive T cells specific for their own antigens can evade immune regulation. Through repeated stimulation of homologous autoantigens, these cells are finally differentiated into T EM and T EMRA cells. Therefore, these autoreactive T cells related to diseases are mainly T EM and T EMR cells. According to the types of cytokines they produce, they can be specifically classified into Th1 and/or Th17 cells [Beeton et al. PNAS 2006,103:17414-17418].
  • PAP-1 Another Kv1.3 small molecule blocker, PAP-1, can effectively inhibit allergic contact dermatitis (ACD) when applied to the local skin model of rats [Azam et al,J Invest Dermatal 2007,127(6):1419 -1427].
  • ACD allergic contact dermatitis
  • injection or topical application of PAP-1 to the skin can reduce the thickness of the diseased epidermal hyperplasia by about 50%, and reduce the infiltration of CD3 + lymphocytes by 85%, which is significant sexually improved the symptoms of psoriasis [Kun clu-Raychaudhuri et al,J Antoimmun 2014,55:63-72].
  • Figure 1 is a graph showing the effect of compound 28 on a rat model of atopic dermatitis (ACD).
  • Figure 2 is a graph showing the effect of compound 29 on imiquimod-induced psoriasis in a rat model, where Figure A is the PASI score result, and Figure B is the Baker score result. Both PASI and Baker score results prove that Compound 29 has an effect on silver Scoria has a significant effect.
  • An object of the present invention is to provide an N-heteroarylsulfonamide derivative characterized in that it is an N-heteroarylsulfonamide compound represented by general formula (I) or general formula (II) or Its pharmaceutically acceptable salt or solvate,
  • Ring A is selected from containing 1-2 substituted five-membered or six-membered aromatic heterocycles containing O, N and S, and the substituted substituents are selected from And R 3 group; wherein ring A is preferably the following five-membered or six-membered aromatic heterocycle:
  • Ring B is selected from substituted or unsubstituted and contains 1-2 five-membered or six-membered alicyclic groups selected from O, N and S, and the substituted substituents are selected from Z and R 4 ; wherein ring B is preferably Said five-membered or six-membered aliphatic heterocyclic ring containing oxygen and/or nitrogen:
  • R 1 is selected from C1-6 linear, branched chain alkyl, cyclic alkyl or halogenated C1-6 linear, branched alkyl, unsubstituted or substituted phenyl or containing 1-2 nitrogen atoms
  • Five-membered or six-membered aromatic heterocyclic ring, benzene ring or aromatic heterocyclic ring is substituted with mono-, di- or tri-substituted, and the substituent is selected from the Ra group;
  • Ra is selected from H, halogen, nitro, cyano, C1-3 alkyl, C1-3 alkoxy, -C-O-C-;
  • R 2 is selected from unsubstituted or substituted phenyl, containing 1-2 five-membered or six-membered aromatic heterocycles selected from O, N and S, and the substitution is mono-substituted, di-substituted or tri-substituted, said substituent Selected from Rb groups;
  • Rb is selected from H, halogen, cyano, C1-3 alkyl, C1-3 alkoxy, -C-O-C-;
  • R 3 is selected from H, cyano, trifluoromethyl, alkamido
  • E, W, X, Y the same or different, each independently selected from N, O, S or C;
  • N-heteroarylsulfonamide derivatives of the present invention are preferably the following compounds:
  • Another object of the present invention is to provide a preparation method of the compound represented by general formula (I) or general formula (II), which can be achieved by the following steps:
  • 2-halo-5-nitropyridine is condensed with a nitrogen-containing five-membered or six-membered alicyclic heterocycle (ring B) under alkaline conditions, and the nitro group in the resulting condensate is condensed on palladium on carbon and/or stannous chloride Reduce to amino in the presence of;
  • the amino compound is then reductively aminated with aromatic aldehydes (selected substituted benzaldehyde, picolinaldehyde, pyrimidine formaldehyde or N-trifluoromethylpyrazole formaldehyde) to obtain N-benzyl derivatives, and then sulfonamidated to obtain the target Molecule: If there is a protective group on the B ring of the obtained sulfonamide molecule, it is then deprotected and derivatized with a terminal hydroxyl or amine group to obtain the target compound.
  • aromatic aldehydes selected substituted benzaldehyde, picolinaldehyde, pyrimidine formaldehyde or N-trifluoromethylpyrazole formaldehyde
  • 2-halo-5-nitropyridine reacts with N-substituted 4-hydroxyl or 4-mercapto or 4-aminopiperidine under alkaline conditions, then reduces the nitro group to an amino group, and then undergoes reductive amination to form a sulfonamide To get the target molecule.
  • the amino five-membered aromatic heterocyclic derivative is reductively aminated and sulfonamidated to obtain the target molecule; if there is a protective group on the B ring of the obtained sulfamidated product, the protective group is then deprotected and an acyl group is introduced into the ring to obtain the target Compound
  • Another object of the present invention is to provide the use of N-arylheterosulfonamide derivatives in the preparation of drugs for the treatment of autoimmune diseases.
  • the autoimmune disease is an autoimmune disease mediated by Kv1.3.
  • the N-arylheterosulfonamide derivatives provided by the present invention can specifically bind to and inhibit or reduce the activity of potassium channel Kv1.3, and can be used as selective Kv1.3 potassium channel inhibitors for the treatment of autoimmune diseases .
  • the medicament for treating autoimmune diseases comprises at least one active ingredient and one or more pharmaceutically acceptable carriers or excipients, and the active ingredient is of general formula (I) or general formula (II) Any one or more of the shown N-arylheterosulfonamide compounds, their pharmaceutically acceptable salts, and their solvates.
  • the carrier or excipient includes conventional diluents, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants, etc. in the pharmaceutical field, and flavors can also be added if necessary.
  • the drug of the present invention can be made into various forms such as tablets, capsules, patches, emulsions, suspensions, gels, powders, granules, oral liquids and injections.
  • the above-mentioned drug in each dosage form can be in accordance with the pharmaceutical field Prepared by conventional methods.
  • the salt of the N-arylheterosulfonamide compound described in the present invention can be prepared by using methods well known to those skilled in the art.
  • the salt may be an inorganic acid salt, an organic acid salt, etc.
  • the inorganic acid salt may be formed with hydrohalic acid (such as hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrochloric acid), nitric acid, carbonic acid, sulfuric acid, phosphoric acid, etc.
  • the corresponding salt; the organic acid salt includes malic acid, L-malic acid, D-malic acid, citric acid, fumaric acid, oxalic acid, lactic acid, camphorsulfonic acid, L-camphorsulfonic acid, D-camphorsulfonic acid Acid, p-toluenesulfonic acid, methanesulfonic acid, benzoic acid, etc. form corresponding salts.
  • the present invention also provides any compound represented by general formula (I) or general formula (II) and its pharmaceutically acceptable salt or solvate used alone and/or in combination with other drugs in the preparation of drugs for the treatment of autoimmune diseases Applications.
  • the present invention also provides a medicament for treating autoimmune diseases, the medicament comprising an N-arylheterosulfonamide compound represented by general formula (I) or general formula (II) or a pharmaceutically acceptable salt thereof or Solvates are used as active components.
  • the present invention also provides a method for the treatment of immune diseases, which administers an effective amount of the N-arylheterosulfonamide compound represented by the general formula (I) or the general formula (II) to patients in need of treatment of autoimmune diseases Or a pharmaceutically acceptable salt or solvate thereof.
  • Kv1.3 potassium channel has been regarded as an important target for the treatment of autoimmune diseases. Therefore, selective Kv1.3 potassium channel inhibitors can be used to treat autoimmune diseases.
  • the autoimmune diseases include psoriasis, psoriatic arthritis, allergic and irritant contact dermatitis, atopic dermatitis, vitiligo, rheumatoid arthritis, type I diabetes, multiple sclerosis, Asthma, glomerulonephritis, periodontal disease, ciliary planitis, transplant rejection, neurodegeneration, obesity, high blood pressure.
  • the present invention has been confirmed through experiments that the N-heteroarylsulfonamide derivatives of the present invention can selectively inhibit the activity of Kv1.3 potassium channels and can be applied to treat human or animal autoimmunity caused by abnormal activation of Kv1.3 potassium channels Disease medicine.
  • the present invention also provides drugs and pharmaceutical compositions containing the N-heteroarylsulfonamide derivatives.
  • Dissolve 1a (2.0 g, 9.6 mmol) in 20 mL of acetic acid, add 0.2 g of 10% palladium on carbon, and hydrogenate at 30° C. for 1 h. After the reaction is over, filter, and the filtrate is directly thrown into the step reaction.
  • Benzaldehyde (1.02g, 9.6mmol) was added to the filtrate, stirred at room temperature for 1h, then cooled to about 10°C, sodium borohydride (0.55g, 14.4mmol) was added, and after the addition, the temperature was kept at this temperature for 30min.
  • the reaction solution was poured into water, the sodium carbonate solution was basified, extracted with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the synthesis steps refer to step 2 of Example 1, except that 2a-5a and p-fluorobenzaldehyde are used as raw materials to prepare compounds 2c-5c.
  • the synthesis procedure refers to step 3 of Example 1, except that 2c-5c and propanesulfonyl chloride are used as raw materials to prepare compound 2-5.
  • the synthesis procedure refers to step 1 in Example 1, except that 2a and the corresponding aromatic aldehyde/heteroaromatic aldehyde are used as raw materials to prepare compound 6c-12c
  • the synthesis procedure refers to step 3 of Example 1, except that 6c-12c and the corresponding sulfonyl chloride are used as raw materials to prepare compound 6-12.
  • the synthesis procedure refers to step 3 of Example 1, except that 4c and 4-fluorobenzenesulfonyl chloride are used as raw materials to prepare compound 13.
  • Dissolve 22a (3.0g 11.3mmol) in 100 mL of methanol, add 0.6g of 10% palladium on carbon, and hydrogenate and reduce at 30°C for 1 hour. After the reaction is completed, it is filtered under reduced pressure, and the filtrate is concentrated and directly thrown into the step reaction. Dissolve the above concentrate in 150mL of acetic acid, add p-fluorobenzaldehyde (1.8g, 14.5mmol) and 1.8g molecular sieve, stir at room temperature for 1h, cool to 10-15°C, add sodium borohydride (0.47g, 12.4mmol), After the addition, the reaction was incubated for 0.5h.
  • Dissolve 29a (15.0g54.0mmol) in 150mL of acetic acid, add 1.6g of 10% palladium on carbon, and hydrogenate and reduce at 30°C for 1h. After the reaction, the filtrate was filtered under reduced pressure, and the filtrate was directly thrown into the step reaction. 4-fluorobenzaldehyde (8.9g, 72.0mmol) was added to the filtrate, stirred at room temperature for 1h, then cooled to about 10°C, and sodium borohydride (4.13g, 108.0mmol), the reaction was incubated for 30min after the addition.
  • Dissolve 29c (12.0 g, 32.5 mmol) in 100 mL of dichloromethane, add pyridine (14.15 g, 179.0 mmol) and propanesulfonyl chloride (4.65 g, 32.5 mmol), and react at room temperature for 6 hours.
  • the synthesis procedure refers to steps 1-3 in Example 9, except that 1-(cyclopropylmethyl)piperazine was used instead of tert-butyl piperazine-1-carboxylate to prepare compound 35.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 46 is used as a raw material to react with ethyl chloroformate, dimethylcarbamoyl chloride, dimethylaminosulfonyl chloride, acetyl chloride, and methanesulfonyl chloride to prepare compounds 47-51.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 52a was reacted with propanesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, and cyclopropylmethylsulfonyl chloride to prepare compounds 52-54.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 55a was reacted with 4-fluorobenzenesulfonyl chloride and propanesulfonyl chloride to prepare compounds 55 and 56.
  • Dissolve 57a (2.1g, 6.79mmol) in 25mL of methanol, add 0.22g of 10% palladium on carbon, and hydrogenate and reduce at room temperature for 3h. After the reaction is over, filter, and the filtrate is directly thrown into the step reaction. 4-fluorobenzaldehyde (0.58g, 6.8mmol) was added to the filtrate, stirred at room temperature for 1.5h, then cooled to about 10°C, sodium borohydride (0.55g, 14.4mmol) was added, and the reaction was kept at this temperature for 30 minutes.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 57 is used as a raw material to react with ethyl chloroformate, dimethylcarbamoyl chloride, dimethylaminosulfonyl chloride, acetyl chloride, and methanesulfonyl chloride to prepare compounds 58-62.
  • Step 2 The synthesis steps refer to Preparation Example 18. Step 2, except that 63a, 64a and 4-fluorobenzaldehyde are used as raw materials to prepare 63c, 64c.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 63c, 64c and propanesulfonyl chloride are used as raw materials to prepare compounds 63 and 64.
  • Step 5 The synthesis steps refer to Example 9. Step 5, except that 65 and acetyl chloride are used as raw materials to prepare compound 66 with a yield of 80.6%.
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 67a and propanesulfonyl chloride are used as raw materials to prepare compound 67 with a yield of 53.0%
  • Step 3 The synthesis steps refer to Example 1. Step 3, except that 68a and 69a were reacted with propanesulfonyl chloride to prepare compounds 68 and 69.
  • the compound's Kv1.3 inhibitory activity was evaluated using a CHO-K1 recombinant cell line (Charles River, California) stably expressing human Kv1.3.
  • the cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • 5% calf serum F-12K medium Invitrogen, Carlsbad, CA
  • treat the adherent cells with Versene at 37°C for 6-7 minutes. After gently tapping the culture flask, resuspend the cells in PBS phosphate buffer, and then centrifuge at 50x g for 4 minutes . After a brief grinding, the cells were finally resuspended in the external recording solution at a density of approximately 1 ⁇ 10 6 /ml.
  • the final concentration gradient of 300 ⁇ was made on the master plate.
  • the final measured gradient concentrations were 0.00384, 0.00192, 0.096, 0.048, 0.24, 1.2, 6 and 30 ⁇ M.
  • the compound measurement plate was sealed and stored at -80°C until the day of measurement.
  • the compound assay plate was thawed at room temperature, and after centrifugation, 198 ⁇ l of external recording solution (its components: 130mM Na-Gluconate, 20mM NaCl, 4mM KCl, 1mM MgCl 2 , 1.8mM CaCl 2 , 5mM Glucose and 10mM HEPES, pH 7.3) and mix well.
  • This step provides a 1:100 dilution of compound. After adding cells to IonWorks, it is further diluted 1:3, so the total dilution is 1:300.
  • At least 8 wells on each assay plate are reserved for blank control, that is, only containing 0.3% DMSO, and at least 8 wells are reserved for positive control to detect the specificity of cell signals.
  • the compound used for the positive control was Fluoxetine, which was tested at its maximum blocking concentration (100 ⁇ M) and the second maximum blocking concentration (10 ⁇ M). Further, inside the recording test solution (having a composition: 100mM K-Gluconate, 40mM KCl , 1mM MgCl 2, 1mM EGTA and 10mM HEPES, pH7.3) containing a final concentration of 200 ⁇ g / ml amphotericin B ( Amphotericin B) to obtain the current channel in the cell. The osmotic pressure of the solution is adjusted with sucrose.
  • the experimental steps are carried out in accordance with the procedures set by the IonWorks Quattro system (Molecular Devices, San Jose, CA).
  • the current of human body Kv1.3 is induced to 0 millivolt (mV) by a pulse lasting 1 second, which is induced four times.
  • a potential of -80 mV is maintained between multiple pulses for 5 seconds.
  • the IonWorks Quattro system starts the pre-voltage application program, then adds the compound and incubates for 600 seconds. Then start the post-voltage application program until the entire test process is completed.
  • the maximum outward peak current was measured before and after the compound addition and the average terminal current induced when the fourth pulse rose to 0 mV was measured.
  • the current amplitude measured after the compound is added is divided by the current amplitude before the compound is added to calculate the compound's inhibitory activity against Kv1.3.
  • the filtering criteria are: sealing quality>30M ⁇ , sealing resistance drop ⁇ 50% and current amplitude>200pA.
  • the compound's Kv1.3 inhibitory activity was evaluated using a CHO-K1 recombinant cell line (Charles River, California) stably expressing human Kv1.3.
  • the cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • the adherent cells were placed in the recording chamber under the inverted microscope. All experiments were performed at room temperature. Each cell uses itself as a control.
  • Extracellular fluid NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the compounds were perfused with a perfusion system using its own gravity. At least two cells are tested per compound concentration. After the current is stable, compare the current changes before and after the compound is used to calculate the blocking effect of the compound.
  • the positive control used 1000 ⁇ M 4-AP.
  • the cells are transferred to the perfusion tank and perfused with extracellular fluid.
  • the intracellular fluid (mM) is: K-aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; pH 7.2 (KOH titration).
  • the intracellular fluid was stored in a small amount in a -80 degree refrigerator in batches and melted on the day of the experiment.
  • the electrode was drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered at one-fifth of the sampling frequency.
  • the compound's Kv1.5 inhibitory activity was evaluated using CHO-K1 recombinant cells stably expressing human Kv1.5. Strain (Charles River, California). The cells were cultured in an incubator containing 5% calf serum F-12K medium (Invitrogen, Carlsbad, CA) at 37° C. and an air humidity containing 6% CO 2 .
  • the adherent cells were placed in the recording chamber under the inverted microscope. All experiments were performed at room temperature. Each cell uses itself as a control.
  • Extracellular fluid NaCl, 137; KCl, 4; CaCl 2 , 1.8; MgCl 2, 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration). All test compound and control compound solutions contained 0.3% DMSO.
  • the compounds were perfused with a perfusion system using its own gravity. At least two cells are tested per compound concentration. After the current is stable, compare the current changes before and after the compound is used to calculate the blocking effect of the compound.
  • the positive control used 1000 ⁇ M 4-AP.
  • the cells are transferred to the perfusion tank and perfused with extracellular fluid.
  • the intracellular fluid (mM) is: K-aspartate, 130; MgCl 2 , 5; EGTA 5; HEPES, 10; pH 7.2 (KOH titration).
  • the intracellular fluid was stored in a small amount in a -80 degree refrigerator in batches and melted on the day of the experiment.
  • the electrode was drawn with PC-10 (Narishige, Japan). Whole-cell patch clamp recording, noise is filtered at one-fifth of the sampling frequency.
  • Dexamethasone DXMS Sodium Phosphate Injection, 5mg/ml/bottle (Shiyao Yinhu Pharmaceutical Co., Ltd.); 1-Chloro-2,4-Dinitrobenzene (DNCB) (Tishai (Shanghai) Chemical Industry Co., Ltd.) Development Co., Ltd.); drug solvent and negative control: acetone/DMSO 9:1 (Vehicle, Model group).
  • mice were randomly divided into 3 groups according to their body weight, each with 10 animals, namely the negative control group (Vehicle), the positive control group (dexamethasone sodium phosphate injection 5mg/ml) and the 5% compound 28 group.
  • DNCB acetone DMSO solution (acetone-DMSO 9:1) was used to sensitize and stimulate the skin of rats to establish a rat model of allergic contact dermatitis (ACD).
  • the rats were normally fed in the SPF barrier system for 1 week.
  • the abdomen was depilated with depilatory cream, with a range of about 2cm ⁇ 2cm.
  • the depilated area was evenly coated with 50 ⁇ L of 7% DNCB acetone DMSO solution to sensitize the experiment.
  • 50 ⁇ L of 1% DNCB acetone DMSO solution was used to reinforce the sensitization once.
  • the rats’ right ear was dripped with 20 ⁇ L of 1% DNCB acetone DMSO solution for excitation, and the left ear was dripped with 20 ⁇ L of acetone DMSO (acetone-DMSO 9:1) solution as a control; Coated with 20 ⁇ L of acetone DMSO solution (9:1) as a control, the rat ears showed obvious erythema and swelling for 3 consecutive days, and a DNCB-induced ACD rat model was prepared.
  • Right ear rubbing administration the first administration 8h before the challenge, and three times a day after the challenge, 25 ⁇ l each time, continuous administration for 7 days; the right ear of the negative control group and the model control group were rubbed with blank matrix in equal volume .
  • Dexamethasone DXMS Sodium Phosphate Injection, 5mg/ml/bottle (Shiyao Yinhu Pharmaceutical Co., Ltd.); 5% Imiquimod cream, 0.25g/bag (Sichuan Mingxin Pharmaceutical Co., Ltd.); 300 Ten thousand U recombinant human interferon ⁇ -2a injection, 1.0ml/bottle (Shenyang Sansheng Pharmaceutical Co., Ltd.); drug solvent and negative control: acetone/DMSO 9:1 (Vehicle).
  • DXMS Dexamethasone
  • mice were randomly divided into 3 groups according to their body weight, each with 10 animals, namely the Normal group, the Model group and the 0.5% compound 29 group.
  • PESI score Skin lesion area and severity index (PASI) score: According to the PASI scoring standard, scores of 0-4 for erythema, scale and epidermal infiltration and thickening at the skin lesions of rats are given. The scoring criteria are as follows: 0, none; 1, mild; 2, moderate; 3, severe; 4, extremely severe. Take the average of the points of each group of rats, and observe the changes of the skin lesions of each group of rats.
  • HE staining After modeling (day 11), the rat back skin lesions are taken, fixed with 4% neutral formaldehyde, embedded in paraffin, and sectioned. After HE staining, observe the morphological changes of the skin tissue under a microscope. Baker score. The Baker scoring criteria are as follows: Munro small abscess found in the epidermis is 2.0 points; hyperkeratosis is 0.5 points; incomplete keratosis is 1.0 points; the granular layer thins or disappears 1.0 points; the spinous layer thickens 1.0 points; Mild, moderate and severe scores are respectively 0.5 points, 1.0 points, and 1.5 points.
  • the infiltration of mononuclear or multinucleated cells in the dermis was scored 0.5 points, 1.0 points, and 1.5 points according to the degree of mild, moderate and severe; 0.5 points for the upper mastoid and 0.5 points for telangiectasia.

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Abstract

La présente invention concerne un dérivé de N-hétéroaryl sulfonamide, une préparation et une utilisation associées. Le dérivé de N-hétéroaryl sulfonamide est un composé de N-hétéroaryl sulfonamide représenté par la formule générale (I) ou la formule générale (II), ou un sel pharmaceutiquement acceptable ou un solvate de celui-ci. Il est confirmé par des expériences que le dérivé de N-hétéroaryl sulfonamide fourni par la présente invention peut se lier de manière spécifique et inhiber ou réduire l'activité du canal potassique Kv1,3, de sorte que le dérivé peut être utilisé pour traiter des maladies auto-immunes, provoquées par une activation anormale du canal potassique Kv1,3, d'un être humain ou d'un animal. La présente invention concerne également un procédé de préparation du dérivé de N-hétéroaryl sulfonamide, ainsi qu'un médicament et une composition pharmaceutique contenant le dérivé de N-hétéroaryl sulfonamide.
PCT/CN2020/073362 2019-01-22 2020-01-21 Dérivé de n-hétéroaryl sulfonamide, préparation et utilisation associées dans le traitement de maladies auto-immunes WO2020151686A1 (fr)

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CN101389622A (zh) * 2006-01-20 2009-03-18 诺瓦提斯公司 用作pi-3激酶抑制剂的嘧啶衍生物
WO2010023445A1 (fr) * 2008-08-29 2010-03-04 Xention Limited Nouveau bloquant du canal potassique
WO2010130638A1 (fr) * 2009-05-14 2010-11-18 Evotec Ag Composés sulfamides, compositions pharmaceutiques et leurs utilisations
CN109705033A (zh) * 2019-01-22 2019-05-03 杭州壹瑞医药科技有限公司 N-杂芳基磺酰胺类衍生物及制备和应用

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CN107459519A (zh) * 2016-06-06 2017-12-12 上海艾力斯医药科技有限公司 稠合嘧啶哌啶环衍生物及其制备方法和应用

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Publication number Priority date Publication date Assignee Title
CN101389622A (zh) * 2006-01-20 2009-03-18 诺瓦提斯公司 用作pi-3激酶抑制剂的嘧啶衍生物
WO2010023445A1 (fr) * 2008-08-29 2010-03-04 Xention Limited Nouveau bloquant du canal potassique
WO2010130638A1 (fr) * 2009-05-14 2010-11-18 Evotec Ag Composés sulfamides, compositions pharmaceutiques et leurs utilisations
CN109705033A (zh) * 2019-01-22 2019-05-03 杭州壹瑞医药科技有限公司 N-杂芳基磺酰胺类衍生物及制备和应用

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